Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid for the treatment of disease

ABSTRACT

The present invention relates to crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, pharmaceutical compositions and dosage forms comprising the crystalline forms, methods of making the crystalline forms and methods for their use for the treatment, prevention or management of diseases ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay.

This application is a continuation of U.S. application Ser. No.16/015,389, filed Jun. 22, 2018, currently allowed, which is acontinuation of U.S. application Ser. No. 15/068,792, filed Mar. 14,2016, now U.S. Pat. No. 10,028,939, issued Jul. 24, 2018, which is acontinuation of U.S. application Ser. No. 14/261,774, filed Apr. 25,2014, now U.S. Pat. No. 9,309,206, issued Apr. 12, 2016, which is acontinuation of U.S. application Ser. No. 13/764,807, filed Feb. 12,2013, now U.S. Pat. No. 8,748,625, issued Jun. 10, 2014, which is acontinuation of U.S. application Ser. No. 12/913,213, filed Oct. 27,2010, now U.S. Pat. No. 8,394,966, issued Mar. 12, 2013, which is adivision of U.S. application Ser. No. 11/904,005, filed Sep. 24, 2007,now U.S. Pat. No. 7,863,456, issued Jan. 4, 2011, which claims thebenefit of U.S. provisional application No. 60/847,326, filed Sep. 25,2006, each of which is incorporated by reference herein in its entirety.

1. FIELD

The present invention relates to crystalline forms of the compound3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid,pharmaceutical dosage forms and compositions comprising the crystallineforms, methods of making the crystalline forms and methods for their usefor the treatment, prevention and management of diseases ameliorated bymodulation of premature translation termination or nonsense-mediatedmRNA decay.

2. BACKGROUND

1,2,4-oxadiazole compounds useful for the treatment, prevention ormanagement of diseases ameliorated by modulation of prematuretranslation termination or nonsense-mediated mRNA decay as described inU.S. Pat. No. 6,992,096 B2, issued Jan. 31, 2006, which is incorporatedherein by reference in its entirety. One such compound is3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

Solid forms such as salts, crystal forms, e.g., polymorphic forms of acompound are known in the pharmaceutical art to affect, for example, thesolubility, stability, flowability, fractability, and compressibility ofthe compound as well as the safety and efficacy of drug products basedon the compound, (see, e.g., Knapman, K. Modern Drug Discoveries,2000:53). So critical are the potential effects of solid forms in asingle drug product on the safety and efficacy of the respective drugproduct that the United States Food and Drug Administration requires theidentification and control of solid forms, e.g., crystalline forms ofeach compound used in each drug product marketed in the United States.Accordingly, new crystalline forms of 1,2,4-oxadiazole benzoic acids canfurther the development of formulations for the treatment, prevention ormanagement of disease ameliorated by modulation of premature translationtermination or nonsense-mediated mRNA decay. The present inventionprovides such novel crystalline forms, for example, crystalline forms of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY

The invention provides novel crystalline forms of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, which has thefollowing chemical structure (I):

In particular, crystalline forms of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid are useful forthe treatment, prevention or management of diseases ameliorated bymodulation of premature translation termination or nonsense-mediatedmRNA decay, said diseases being described in U.S. Pat. No. 6,992,096 B2,issued Jan. 31, 2006, which is incorporated herein by reference in itsentirety. In addition, the present provides a crystalline form of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid which issubstantially pure, i.e., its purity greater than about 90%.

Certain embodiments of the invention provide pharmaceutical dosage formsand compositions comprising a crystalline form of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid and apharmaceutically-acceptable diluent, excipient or carrier. The inventionfurther provides methods of their use for the treatment, prevention ormanagement of diseases ameliorated by modulation of prematuretranslation termination or nonsense-mediated mRNA decay. In certainembodiments, the invention provides methods of making, isolating and/orcharacterizing the crystalline forms of the invention. The crystallineforms of the invention are useful as active pharmaceutical ingredientsfor the preparation of formulations for use in animals or humans. Thus,the present invention encompasses the use of these crystalline forms asa final drug product. The crystalline forms and final drug products ofthe invention are useful, for example, for the treatment, prevent ormanagement of the diseases described herein.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Brief Description of theDrawings

FIG. 1 provides an X-ray powder diffraction (XRPD) pattern of a samplecomprising Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

FIG. 2 provides differential scanning calorimetry (DSC) andthermogravimentric analysis (TGA) thermograms of a sample comprisingForm A of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

FIG. 3 provides a dynamic vapor sorption (DVS) isotherm of a samplecomprising Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

FIG. 4 provides a solid-state ¹³C NMR spectrum of a sample comprisingForm A of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

FIG. 5 provides a XRPD pattern of a sample comprising Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

FIG. 6 provides DSC and TGA thermograms of a sample comprising Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

FIG. 7 provides a DVS isotherm of a sample comprising Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

FIG. 8 provides an overlay of experimental XRPD patterns showing acharacteristic peak set of Form A (Top) with respect to several samplescomprising Form B (second from top to bottom) of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, illustratingpeak shift among certain Form B samples.

FIG. 9 provides crystal packing diagram of Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, viewed downthe crystallographic b axis and showing an outline of the unit cell.

FIG. 10 provides a XRPD pattern of Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid simulated froma single-crystal X-ray diffraction crystal structure obtained from arepresentative single crystal of Form A.

FIG. 11 provides a ORTEP plot of the asymmetric unit of thesingle-crystal XRD crystal structure of Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid. Atoms arerepresented by 50% probability anisotropic thermal ellipsoids.

4.2 Terminology

Crystalline forms equivalent to the crystalline forms described belowand claimed herein may demonstrate similar, yet non-identical,analytical characteristics within a reasonable range of error, dependingon test conditions, purity, equipment and other common variables knownto those skilled in the art or reported in the literature. The term“crystalline” and related terms used herein, when used to describe asubstance, component or product, means that the substance, component orproduct is substantially crystalline as determined by X-ray diffraction,microscopy, polarized microscopy, or other known analytical procedureknown to those skilled in the art. See, e.g., Remington's PharmaceuticalSciences, 18th ed., Mack Publishing, Easton Pa., 173 (1990); The UnitedStates Pharmacopeia, 23rd ed., 1843-1844 (1995).

Accordingly, it will be apparent to those skilled in the art thatvarious modifications and variations can be made in the presentinvention without departing from the scope and spirit of the invention.Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. Applicants intend that the specification andexamples be considered as exemplary, but not limiting in scope.

The crystalline forms of the instant invention can be characterizedusing Single Crystal Data, Powder X-Ray Diffraction (PXRD), DifferentialScanning Calorimetry (DSC), and Thermogravimetric Analysis (TGA). It isto be understood that numerical values described and claimed herein areapproximate. Variation within the values may be attributed to equipmentcalibration, equipment errors, purity of the materials, crystals size,and sample size, among other factors. In addition, variation may bepossible while still obtaining the same result. For example, X-raydiffraction values are generally accurate to within .+−.0.2 degrees andintensities (including relative intensities) in an X-ray diffractionpattern may fluctuate depending upon measurement conditions employed.Similarly, DSC results are typically accurate to within about 2° C.Consequently, it is to be understood that the crystalline forms of theinstant invention are not limited to the crystalline forms that providecharacterization patterns (i.e., one or more of the PXRD, DSC, and TGA)completely identical to the characterization patterns depicted in theaccompanying Figures disclosed herein. Any crystalline forms thatprovide characterization patterns substantially the same as thosedescribed in the accompanying Figures fall within the scope of thepresent invention. The ability to ascertain substantially the samecharacterization patterns is within the purview of one of ordinary skillin the art.

The embodiments provided herein can be understood more fully byreference to the following detailed description and illustrativeexamples, which are intended to exemplify non-limiting embodiments.

Processes for the preparation of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid are describedin U.S. Pat. No. 6,992,096 B2, issued Jan. 31, 2006, and U.S. patentapplication Ser. No. 11/899,813, filed Sep. 9, 2007, both of which areincorporated by reference in their entirety.

4.3 Form A of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic Acid

In one embodiment, the present invention provides the Form A crystalform of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid. Incertain embodiments, Form A can be obtained by crystallization fromvarious solvents, including, but not limited to, methanol,tertiary-butyl alcohol (t-BuOH), 1-butyl alcohol (1-BuOH), acetonitrile,isopropyl alcohol (IPA), isopropyl ether, dimethyl formamide, heptane,isopropyl acetate (IPOAc), toluene and/or water. A representative XRPDpattern of Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid is provided inFIG. 1. In certain embodiments, Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid has an XRPDpattern which is substantially similar to the pattern displayed in FIG.1.

Representative thermal characteristics of Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid are shown inFIG. 2. A representative DSC thermogram, presented in FIG. 2, exhibitsan endothermic event with a peak temperature at about 244° C. Arepresentative TGA thermogram, also presented in FIG. 2, exhibits a massloss of less than about 1% of the total mass of the sample upon heatingfrom about 33° C. to about 205° C. These thermal data indicate that FormA of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid does notcontain substantial amounts of either water or solvent in the crystallattice. In certain embodiments, Form A exhibits a TGA weight loss eventcommencing at about 212° C. which corresponds to sublimation prior tomelting.

A single-crystal X-ray diffraction (XRD) crystal structure was obtainedfrom a representative single crystal of Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid. Using XRDdata collected at about 150 K, the following unit cell parameters wereobtained: a=24.2240(10) Å; b=3.74640(10) Å; c=27.4678(13) Å; α=90°;β=92.9938(15)°; γ=90°; V=2489.38(17) Å³. A crystal packing diagram fromthe single-crystal XRD structure of Form A, viewed down thecrystallographic b axis, is provided as FIG. 9. A simulated XRPD patternwas generated for Cu radiation using PowderCell 2.3 (PowderCell forWindows Version 2.3 Kraus, W.; Nolze, G. Federal Institute for MaterialsResearch and Testing, Berlin Germany, E U, 1999) and the atomiccoordinates, space group, and unit cell parameters from the singlecrystal data. A simulated XRPD pattern of Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid is provided asFIG. 10.

In certain embodiments, Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ischaracterized by its physical stability when subjected to certainprocessing conditions. In certain embodiments, Form A is physicallystable when stored for 6 days at one or more of the following relativehumidity (RH) conditions: 53% RH at 40° C.; 75% RH at 40° C.; 50% RH at60° C.; and 79% RH at 60° C. In other embodiments, Form A is physicallystable when milled at ambient and at sub-ambient temperatures. In otherembodiments, Form A is physically stable when slurried at one or more ofthe following conditions: in 1-BuOH for 4 days at ambient temperature;in chloroform for 2 days at 50° C.; and in dichloromethane for 2 days at50° C.

Form A of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid wasevaluated for hygroscopicity. Dynamic vapor sorption (DVS) analysis ofmoisture uptake and moisture release as a function of relative humidity(RH) were obtained upon cycling between 5% and 95% RH. The maximumuptake was about 0.06% of the total mass of the sample, as demonstratedin the representative Form A DVS isotherm in FIG. 3. Accordingly, incertain embodiments, Form A is non-hygroscopic.

A representative ¹³C solid-state NMR spectrum of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid is provided inFIG. 4. In certain embodiments, Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ischaracterized by ¹³C CP/MAS solid-state NMR signals located at one ormore of the following approximate positions: 172.6, 167.0, 131.3, 128.4;and 117.1 ppm, when externally referenced to glycine at 176.5 ppm.

In certain embodiments, Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid exhibitsdesirable characteristics for the processing and/or manufacture of drugproduct containing 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoicacid. For example, in certain embodiments, Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid has arelatively high melting point, which is an important characteristic for,inter alia, processing and manufacturing. Moreover, in certainembodiments, Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid was found tobe substantially non-hygroscopic. A non-hygroscopic solid form isdesirable for a variety of reasons including, for example, forprocessing and storage concerns. Moreover, in certain embodiments, FormA of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid was foundto be physically and chemically stable upon micronization, a method ofparticle size reduction. Physical stability is an important property ofpharmaceutical materials during manufacture, processing, and storage.

4.4 Form B of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic Acid

In one embodiment, the present invention provides the Form B crystalform of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid. Incertain embodiments, Form B can be obtained by crystallization fromvarious solvents, including, but not limited to, tetrahydrofuran (THF),hexane, isopropyl alcohol (IPA) ethyl acetate (EtOAc), acetic acid,1-butyl acetate, acetone, dimethyl ether, diethyl ether, dioxane, water,methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethaneand or water.

In certain embodiments of the invention, Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid has solvent inthe crystal lattice in an amount which depends upon one or moreconditions such as, but not limited to, crystallization, treatment,processing, formulation, manufacturing or storage. In certainembodiments of the invention, Form B has solvent in the crystal lattice.In certain embodiments, Form B is essentially free of solvent in thecrystal lattice. In certain embodiments, the maximum combined molarequivalents of solvent per mole of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid in a sample ofForm B is less than 6, less than 5, less than 4, less than 3, less than2, less than 1.5, less than 1, less than 0.75, less than 0.5, or lessthan 0.25 molar equivalents. Without intending to be limited by theory,it is believed that the characteristic variably in the solvent contentof Form B arises from the existence of a lattice channel which canaccommodate different types and/or amounts of solvent, and which permitsthe addition and/or removal of solvents depending upon the particularconditions. In certain embodiments, the structure of Form B representsthe basis for an isostructural family of crystal forms. In certainembodiments, Form B is a desolvated solvate crystal form.

A representative XRPD pattern of Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid is provided inFIG. 5. In certain embodiments, Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ischaracterized by XRPD peaks located at one or more of the followingpositions: about 6.4, about 8.0, about 14.1, about 15.9, about 17.2 andabout 20.1 degrees 2θ. It is understood by one of skill in the art thatwhen solvents and/or water are added or removed from a crystal lattice,the lattice will slightly expands or contract, resulting in minor shiftsin the position of XRPD peaks. In certain embodiments of the presentinvention, Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid is providedwhich is characterized by an XRPD pattern substantially similar to thepattern displayed in FIG. 5. In certain embodiments, Form B exhibits aXRPD pattern substantially similar to the pattern displayed in FIG. 5but exhibits small shifts in peak positions resulting from the presenceor absence of specific solvents or water in the crystal lattice. Certainrepresentative XRPD patterns of Form B (second from top to bottom) arecompared to Form A (top) of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid in FIG. 8. Incertain embodiments, Form B has a XRPD pattern substantially similar toone or more of the XRPD patterns displayed in FIG. 8.

Thermal characteristics of a sample of Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid crystallizedfrom a 2.5:1 THF:hexane mixture are shown in FIG. 6. A TGA thermogram ofthis Form B sample, presented in FIG. 6, exhibits two mass loss events:one mass loss event of about 5% of the total mass of the sample uponheating from about 25° C. to about 165° C., and a second mass loss eventcommencing at about 220° C. Hotstage microscopy revealed that the firstmass loss event resulted from the loss of solvent and/or water from thecrystal lattice, and the second mass loss event resulted from thesublimation of Form B. XRPD analysis of the resulting sublimateindicated that Form A of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid had formed. ADSC thermogram of this Form B sample, presented in FIG. 6, exhibits asharp endothermic event with a peak temperature at about 243° C.,corresponding to the melt of the Form A sublimate. The DSC of this FormB sample also exhibits at least one other event at a temperature belowabout 220° C. These thermal data indicate that this sample of Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid containedwater and/or solvent in the crystal lattice. On account of the variablewater and/or solvent content of certain samples of Form B of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, in certainembodiments of the invention the thermal characteristics of Form B willexhibit certain variation. For example, in specific embodiments of theinvention, samples of Form B which are essentially free of water andsolvent do not exhibit a substantial TGA mass loss or DSC thermal eventbelow about 220° C. Because Form B sublimes and crystallizes as Form A,thus in FIG. 6, the heat of fusion for the endotherm is after the samplehas converted to Form A.

In one embodiment of the invention, a Form B sample which crystallizedfrom IPA had about 0.1 molar equivalents of IPA and about 1 molarequivalents of water per mole of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, based uponanalysis using TGA and ¹H NMR. In specific embodiments of the invention,a Form B sample which possesses approximately 1 molar equivalent ofwater per molar equivalent of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid is termed amonohydrate. In another embodiment of the invention, a Form B samplewhich was treated by vacuum drying at 105° C. for 10 min exhibited atotal weight loss of 2% of the mass of the sample when subsequentlyanalyzed by TGA from about 25 to about 185° C. In certain embodiments,the Form B characteristics which are dependent upon the quantity and/oridentity of the solvent and/or water in the crystal lattice (e.g., massloss upon heating or drying) will exhibit variation with respect to thetotal quantity or identity of solvent and/or water in the crystallattice. In certain embodiments, regardless of the quantity and/oridentity of solvent and/or water in the crystal lattice, the XRPDpattern of Form B will exhibit peaks characteristic of Form B asdescribed supra, but with minor peak shifting arising from differencesin quantity and/or identity of the solvent and/or water in the Form Bcrystal lattice. Representative XRPD patterns illustrating peak shiftingamong certain Form B samples are overlaid in FIG. 8 (second from top tobottom).

In certain embodiments of the invention, upon milling at ambient orsub-ambient temperatures, conversion from Form B to Form A is observed.In other embodiments of the invention, Form B is physically stable uponstorage for 6 days at one of the following relative humidity (RH)conditions: 53% RH at 40° C.; 75% RH at 40° C.; and 50% RH at 60° C. Inother embodiments of the invention, Form B is substantiallynon-hygroscopic, as illustrated by the representative Form B DVSisotherm in FIG. 7. In other embodiments of the invention, Form Bexhibited partial conversion to Form A upon storage for 6 days at thecondition of 79% RH at 60° C. In other embodiments of the invention,Form B is physically stable under compression alone and undercompression in the presence of a 1:1 mixture of t-BuOH and water. Inother embodiments of the invention, Form B is physically stable whenslurried for 1 day at ambient temperature in a 1:1 mixture of THF andheptane. In other embodiments, conversion of Form B to Form A isobserved upon slurrying Form B in either methyl isobutyl ketone or a 1:1mixture of dioxane and water.

4.5 Methods of Use

Provided herein are methods of treating, preventing and managingdiseases or disorders ameliorated by the suppression of prematuretranslation termination and/or nonsense-mediated mRNA decay in a patientwhich comprise administering to a patient in need thereof an effectiveamount of a solid form of3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.

In one embodiment, provided herein are methods for the treatment,prevention or management of any disease that is associated with a geneexhibiting premature translation termination and/or nonsense-mediatedmRNA decay. In one embodiment, the disease is due, in part, to the lackof expression of the gene resulting from a premature stop codon.Specific examples of genes which may exhibit premature translationtermination and/or nonsense-mediated mRNA decay and diseases associatedwith premature translation termination and/or nonsense-mediated mRNAdecay are found in U.S. Patent Application Publication No. 2005-0233327,titled: Methods For Identifying Small Molecules That Modulate PrematureTranslation Termination And Nonsense Mediated mRNA Decay, which isincorporated herein by reference in its entirety.

Diseases or disorders associated with or ameliorated by the suppressionof premature translation termination and/or nonsense-mediated mRNA decayinclude, but are not limited to: a genetic disease, cancer, anautoimmune disease, a blood disease, a collagen disease, diabetes, aneurodegenerative disease, a proliferative disease, a cardiovasculardisease, a pulmonary disease, an inflammatory disease or central nervoussystem disease.

Specific genetic diseases within the scope of the methods of theinvention include, but are not limited to, multiple endocrine neoplasia(type 1, 2 and 3), amyloidosis, mucopolysaccharidosis (type I and III),congenital adrenal hypoplasia, adenomatous poliposis coli, Von HippelLandau Disease, Menkes Syndrome, hemophilia A, hemophilia B, collagenVII, Alagille Syndrome, Townes-Brocks Syndrome, rhabdoid tumor,epidermolysis bullosa, Hurler's Syndrome, Coffin-Lowry Syndrome,aniridia, Charcot-Maria-Tooth Disease, myotubular myopathy, X-linkedmyotubular myopathy, X-linked chondrodysplasia, X-linkedagammaglobulinemia, polycystic kidney disease, spinal muscular atrophy,familial adenomatous poliposis, pyruvate dehydrogenase deficiency,phenylketonuria, neurofibromatosis 1, neurofibromatosis 2, Alzheimer'sdisease, Tay Sachs disease, Rett Syndrome, Hermansky-Pudlak Syndrome,ectodermal dysplasia/skin fragility syndrome, Leri-Weilldyschondrosteosis, rickets, hypophosphataemic, adrenoleukodystrophy,gyrate atrophy, atherosclerosis, sensorineural deafness, dystonia, DentDisease, acute intermittent porphyria, Cowden Disease, Herlitzepidermolysis bullosa, Wilson Disease, Treacher-Collins Syndrome,pyruvate kinase deficiency, giantism, dwarfism, hypothyroidism,hyperthyroidism, aging, obesity, Parkinson's disease, Niemann Pick'sdisease C, Cystic Fibrosis, muscular dystrophy, heart disease, kidneystones, ataxia-telangiectasia, familial hypercholesterolemia, retinitispigmentosa, lysosomal storage disease, tuberous sclerosis, DuchenneMuscular Dystrophy, and Marfan Syndrome.

In another embodiment, the genetic disease is an autoimmune disease. Ina preferred embodiment, the autoimmune disease is rheumatoid arthritisor graft versus host disease.

In another embodiment, the genetic disease is a blood disease. In aparticular embodiment, the blood disease is hemophilia A, Von Willebranddisease (type 3), ataxia-telangiectasia, b-thalassemia or kidney stones.

In another embodiment, the genetic disease is a collagen disease. In aparticular embodiment, the collagen disease is osteogenesis imperfectaor cirrhosis.

In another embodiment, the genetic disease is diabetes.

In another embodiment, the genetic disease is an inflammatory disease.In a particular embodiment, the inflammatory disease is arthritis.

In another embodiment, the genetic disease is a central nervous systemdisease. In one embodiment the central nervous system disease is aneurodegenerative disease. In a particular embodiment, the centralnervous system disease is multiple sclerosis, muscular dystrophy,Duchenne muscular dystrophy, Alzheimer's disease, Tay Sachs disease,late infantile neuronal ceroid lipofuscinosis (LINCL) or Parkinson'sdisease.

In another embodiment, the genetic disease is cancer. In a particularembodiment, the cancer is of the head and neck, eye, skin, mouth,throat, esophagus, chest, bone, lung, colon, sigmoid, rectum, stomach,prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine,heart or adrenals. The cancer can be primary or metastatic. Cancersinclude solid tumors, hematological cancers and other neoplasias.

In another particular embodiment, the cancer is associated with tumorsuppressor genes (see e.g. Garinis et al. 2002, Hum Gen 111:115-117;Meyers et al. 1998, Proc. Natl. Acad. Sci. USA, 95: 15587-15591; Kung etal. 2000, Nature Medicine 6(12): 1335-1340. Such tumor suppressor genesinclude, but are not limited to, APC, ATM, BRAC1, BRAC2, MSH1, pTEN, Rb,CDKN2, NF1, NF2, WT1, and p53.

In a particularly preferred embodiment, the tumor suppressor gene is thep53 gene. Nonsense mutations have been identified in the p53 gene andhave been implicated in cancer. Several nonsense mutations in the p53gene have been identified (see, e.g., Masuda et al., 2000, Tokai J ExpClin Med. 25(2):69-77; Oh et al., 2000, Mol Cells 10(3):275-80; Li etal., 2000, Lab Invest. 80(4):493-9; Yang et al., 1999, Zhonghua ZhongLiu Za Zhi 21(2): 114-8; Finkelstein et al., 1998, Mol Diagn.3(1):37-41; Kajiyama et al., 1998, Dis Esophagus. 11(4):279-83; Kawamuraet al., 1999, Leuk Res. 23(2):115-26; Radig et al., 1998, Hum Pathol.29(11): 1310-6; Schuyer et al., 1998, Int J Cancer 76(3):299-303;Wang-Gohrke et al., 1998, Oncol Rep. 5(1):65-8; Fulop et al., 1998, JReprod Med. 43(2): 119-27; Ninomiya et al., 1997, J Dermatol Sci.14(3):173-8; Hsieh et al., 1996, Cancer Lett. 100(1-2):107-13; Rall etal., 1996, Pancreas. 12(1):10-7; Fukutomi et al., 1995, Nippon Rinsho.53(11):2764-8; Frebourg et al., 1995, Am J Hum Genet. 56(3):608-15; Doveet al., 1995, Cancer Surv. 25:335-55; Adamson et al., 1995, Br JHaematol. 89(1):61-6; Grayson et al., 1994, Am J Pediatr Hematol Oncol.16(4):341-7; Lepelley et al., 1994, Leukemia. 8(8): 1342-9; McIntyre etal., 1994, J Clin Oncol. 12(5):925-30; Horio et al., 1994, Oncogene.9(4):1231-5; Nakamura et al., 1992, Jpn J Cancer Res. 83(12):1293-8;Davidoff et al., 1992, Oncogene. 7(1):127-33; and Ishioka et al., 1991,Biochem Biophys Res Commun. 177(3):901-6; the disclosures of which arehereby incorporated by reference in their entireties).

In other embodiments, diseases to be treated, prevented or managed byadministering to a patient in need thereof an effective amount of asolid form of 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acidinclude, but are not limited to, solid tumor, sarcoma, carcinomas,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma,melanoma, neuroblastoma, retinoblastoma, a blood-born tumor, acutelymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acutelymphoblastic T-cell leukemia, acute myeloblastic leukemia, acutepromyelocytic leukemia, acute monoblastic leukemia, acuteerythroleukemic leukemia, acute megakaryoblastic leukemia, acutemyelomonocytic leukemia, acute nonlymphocyctic leukemia, acuteundifferentiated leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia, hairy cell leukemia, or multiple myeloma. Seee.g., Harrison's Principles of Internal Medicine, Eugene Braunwald etal., eds., pp. 491-762 (15th ed. 2001).

4.6 Pharmaceutical Compositions

Pharmaceutical compositions and single unit dosage forms comprising acompound of the invention, or a pharmaceutically acceptable polymorph,prodrug, salt, solvate, hydrate, or clathrate thereof, are alsoencompassed by the invention. Individual dosage forms of the inventionmay be suitable for oral, mucosal (including sublingual, buccal, rectal,nasal, or vaginal), parenteral (including subcutaneous, intramuscular,bolus injection, intraarterial, or intravenous), transdermal, or topicaladministration.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. These and other ways in whichspecific dosage forms encompassed by this invention will vary from oneanother will be readily apparent to those skilled in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, EastonPa. (1995).

Typical pharmaceutical compositions and dosage forms comprise one ormore carriers, excipients or diluents. Suitable excipients are wellknown to those skilled in the art of pharmacy, and non-limiting examplesof suitable excipients are provided herein. Whether a particularexcipient is suitable for incorporation into a pharmaceuticalcomposition or dosage form depends on a variety of factors well known inthe art including, but not limited to, the way in which the dosage formwill be administered to a patient. For example, oral dosage forms suchas tablets may contain excipients not suited for use in parenteraldosage forms. The suitability of a particular excipient may also dependon the specific active ingredients in the dosage form.

5. EXAMPLES 5.1 Synthesis of Solid Forms of the of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic Acid

The 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid productobtained from the synthesis described supra may be crystallized orrecrystallized in a number of ways to yield the solid forms of theinvention. Provided below are several non-limiting examples.

5.1.1 Synthesis of Form A 5.1.1.1 Slow Evaporation

The 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid productobtained as described herein was crystallized as Form A by the method ofslow evaporation from the each one of the following solvents:acetonitrile; t-butanol; isopropyl alcohol; and isopropyl ether. Asolution of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acidwas prepared in the indicated solvent and sonicated between aliquotadditions to assist in dissolution. Once a mixture reached completedissolution, as judged by visual observation, the solution was filteredthrough a 0.2-μm filter. The filtered solution was allowed to evaporateat a temperature of 60° C. (50° C. in the case of t-butanol), in a vialcovered with aluminum foil containing pinhole(s). The solids that formedwere isolated and characterized by XRPD as Form A.

5.1.1.2 Fast Evaporation

The 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid productobtained as described herein was crystallized as Form A by the method offast evaporation from each one of the following solvents or solventsystems: 1-butanol; dimethoxyether; t-butanol; a mixture of dimethylformamide and water; isopropyl ether; and a mixture of t-butanol:water(in a 3:2 ratio), 1 molar equivalent methanol and 1 molar equivalentsodium chloride. Solutions were prepared in the indicated solvent orsolvent system and sonicated between aliquot additions to assist indissolution. Once a mixture reached complete dissolution, as judged byvisual observation, the solution was filtered through a 0.2-μm filter.The filtered solution was allowed to evaporate at a temperature of 60°C. (50° C. in the cases of t-butanol and isopropyl ether; 81° C. in thecase of the t-butanol/water/methanol/NaCl system) in an open vial. Thesolids that formed were isolated and characterized by XRPD as Form A.

5.1.1.3 Slurry Conversion

Form B of the free acid of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, obtained asdescribed herein, was converted to Form A by the method of slurrying inthe solvent system 1:1 dioxane:water. A slurry was prepared by addingenough Form B solids to a given solvent so that excess solids werepresent. The mixture was then agitated in a sealed vial at a temperatureof 60° C. After 2 days, the solids were isolated by vacuum filtrationand characterized by XRPD as Form A with a minor amount of Form B.

5.1.1.4 Sublimation and Heating

Form B of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid,obtained as described herein, was converted to Form A by the methods ofsublimation and heating. In one experiment, Form B was sublimed at160-208° C., under vacuum, for 35 minutes to yield white needles whichwere characterized by XRPD as Form A. In another experiment, Form B wasmelted at 255° C., followed by direct placement into liquid nitrogen toyield crystalline material which was characterized by XRPD as Form A. Inanother experiment, Form B was melted at 255° C. and then cooled slowlyto yield crystalline material which was characterized by XRPD as Form A.

5.1.2 Synthesis of Form B 5.1.2.1 Slow Evaporation

The 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid productobtained as described herein was crystallized as Form B by the method ofslow evaporation from each one of the following solvents: acetone;dimethyl ether; and methyl ethyl ketone. A solution of3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid was preparedin the indicated solvent and sonicated between aliquot additions toassist in dissolution. Once a mixture reached complete dissolution, asjudged by visual observation, the solution was filtered through a 0.2-μmfilter. The filtered solution was allowed to evaporate at a temperatureof 50° C. (60° C. in the case of methyl ethyl ketone), in a vial coveredwith aluminum foil containing pinhole(s).

In one embodiment, 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoicacid was dissolved in dimethoxyether. The solution was into a cleanvial. The vial was filtered through a 0.2-μm filter covered withaluminum foil perforated with pinhole(s) and the solvent allowed toevaporate. The solids that formed were isolated and characterized byXRPD as Form B. XRPD analysis is illustrated in Table 8 (P.O.)

5.1.2.2 Fast Evaporation

The 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid productobtained as described herein was crystallized as Form B by the method offast evaporation from each one of the following solvents or solventsystems: acetone, acetic acid, 1-butyl acetate; dimethyl ether; THF anddiethyl ether; dioxane; methyl ethyl ketone; nitromethane; methyliso-butyl ketone; THF:hexane (2.5:1); and dioxane:water (3:2). Solutionswere prepared in the indicated solvent or solvent system and sonicatedbetween aliquot additions to assist in dissolution. Once a mixturereached complete dissolution, as judged by visual observation, thesolution was filtered through a 0.2-μm filter. The filtered solution wasallowed to evaporate at an elevated temperature in an open vial. Thesolids that formed were isolated and characterized by XRPD as Form B.

5.1.2.3 Slurry Conversion

Form A of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid,obtained as described herein, was converted to Form B by the method ofslurrying in each one of the following solvents: acetic acid; 1-butylacetate; and nitromethane. In one embodiment,3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid was slurriedon an orbit shaker in 1-butyl acetate (13 mL) at room temperature for 3days. After three days the solvent was removed by pipette, dried andcharacterized by XRPD as Form B (Table 5)

5.1.2.4 Orbit Shaker Conversion

Form A of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid,obtained as described herein, was converted to Form B by heating on anorbit shaker in 1-propanol (10 mL) at 60° C. for 1 day on an orbitshaker. The resulting solution was through 0.2 jam nylon filter into aclean vial. After 1 day, the solvent was decanted and the sample driedunder nitrogen. XRPD analysis as form B is illustrated in Table 4.

5.1.2.5 Other Embodiments

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (20 mg, FormB) was slurried in a mixture of tetrahydrofuran/heptane 1/1 (2 mL) atambient temperature for 1 day. After 1 day, the slurry was seeded withForm A (10 mg) and Form B (9 mg) and slurried for an additional day,after which time additional Form A (30 mg) was added. After slurryingthe sample a total of 7 days additional Form A was added (30 mg) and thetemperature increased to 50° C. Solids were collected after slurrying at50° C. for one day. The solids that formed were isolated andcharacterized by XRPD as Form B. XRPD analysis is illustrated in Table6.

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (UNMEASUREDQUANTITY; FORM B) was stressed in 75% relative humidity at 40° C. forsix days. The solids that formed were isolated and characterized by XRPDas Form B. XRPD analysis is illustrated in Table 7.

5.2 Analytical Procedures

The following methods of solid-state analysis provide examples of howthe solid forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoicacid of the present invention may be characterized. The specific methodsdescribed below were employed to obtain the solid-state characterizationdata described herein.

5.2.1 X-Ray Powder Diffraction (XRPD)

Certain XRPD analyses were performed using a Shimadzu XRD-6000 X-raypowder diffractometer using Cu Kα radiation. The instrument is equippedwith a long fine focus X-ray tube. The tube voltage and amperage wereset to 40 kV and 40 mA, respectively. The divergence and scatteringslits were set at 1 and the receiving slit was set at 0.15 mm.Diffracted radiation was detected by a NaI scintillation detector. Aθ-2θ continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5 to 40° 2θwas used. A silicon standard was analyzed to check the instrumentalignment. Data were collected and analyzed using XRD-6100/7000 v. 5.0.Samples were prepared for analysis by placing them in a sample holder.

Certain XRPD analyses were performed using an Inel XRG-3000diffractometer equipped with a CPS (Curved Position Sensitive) detectorwith a 2θ range of 120°. Real time data were collected using Cu-Kαradiation at a resolution of 0.03° 2θ. The tube voltage and amperagewere set to 40 kV and 30 mA, respectively. The monochromator slit wasset at 5 mm by 160 μm. The pattern is displayed from 2.5-40° 2θ. Analuminum sample holder with silicon insert was used/or/Samples wereprepared for analysis by packing them into thin-walled glasscapillaries. Each capillary was mounted onto a goniometer head that ismotorized to permit spinning of the capillary during data acquisition.The samples were analyzed for 300 sec. Instrument calibration wasperformed using a silicon reference standard.

Certain XRPD patterns were collected with a Bruker D-8 Discoverdiffractometer and Bruker's General Area Diffraction Detection System(GADDS, v. 4.1.20). An incident beam of Cu Kα radiation was producedusing a fine-focus tube (40 kV, 40 mA), a Göbel mirror, and a 0.5 mmdouble-pinhole collimator. A specimen of the sample was packed in acapillary and secured to a translation stage. A video camera and laserwere used to position the area of interest to intersect the incidentbeam in transmission geometry. The incident beam was scanned to optimizeorientation statistics. A beam-stop was used to minimize air scatterfrom the incident beam at low angles. Diffraction patterns werecollected using a Hi-Star area detector located 15 cm from the sampleand processed using GADDS. The intensity in the GADDS image of thediffraction pattern was integrated using a step size of 0.04° 2θ. Theintegrated patterns display diffraction intensity as a function of 2θ.Prior to the analysis a silicon standard was analyzed to verify the Si111 peak position.

Certain XRPD files generated from Inel XRPD instruments were convertedto Shimadzu .raw file using File Monkey version 3.0.4. The Shimadzu .rawfile was processed by the Shimadzu XRD-6000 version 2.6 software toautomatically find peak positions. The “peak position” means the maximumintensity of a peaked intensity profile. Parameters used in peakselection are shown in the lower half of each parameter set of the data.The following processes were used with the Shimadzu XRD-6000 “BasicProcess” version 2.6 algorithm:

-   -   Smoothing was done on all patterns.    -   The background was subtracted to find the net, relative        intensity of the peaks.    -   A peak from Cu K alpha2 (1.5444 Å) wavelength was subtracted        from the peak generated by Cu K alpha1 (1.5406 Å) peak at 50%        intensity for all patterns.

5.2.2 Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry (DSC) was performed using a TAInstruments differential scanning calorimeter 2920. The sample wasplaced into an aluminum DSC pan, and the weight accurately recorded. Thepan was covered with a lid and then crimped. The sample cell wasequilibrated at 25° C. and heated under a nitrogen purge at a rate of10° C./min, up to a final temperature of 350° C. Indium metal was usedas the calibration standard. Reported temperatures are at the transitionmaxima.

5.2.3 Thermogravimetric Analysis (TGA)

Thermogravimetric (TG) analyses were performed using a TA Instruments2950 thermogravimetric analyzer. Each sample was placed in an aluminumsample pan and inserted into the TG furnace. The furnace was (firstequilibrated at 35° C., then) heated under nitrogen at a rate of 10°C./min, up to a final temperature of 350° C. Nickel and Alumel™ wereused as the calibration standards.

5.2.4 Dynamic Vapor Sorption/Desorption (DVS)

Moisture sorption/desorption data were collected on a VTI SGA-100 VaporSorption Analyzer. Sorption and desorption data were collected over arange of 5% to 95% relative humidity (RH) at 10% RH intervals under anitrogen purge. Samples were not dried prior to analysis. Equilibriumcriteria used for analysis were less than 0.0100% weight change in 5minutes, with a maximum equilibration time of 3 hours if the weightcriterion was not met. Data were not corrected for the initial moisturecontent of the samples. NaCl and PVP were used as calibration standards.

5.2.5 Karl Fischer (KF)

Coulometric Karl Fischer (KF) analysis for water determination wasperformed using a Mettler Toledo DL39 Karl Fischer titrator.Approximately 21 mg of sample was placed in the KF titration vesselcontaining Hydranal—Coulomat AD and mixed for 42-50 seconds to ensuredissolution. The sample was then titrated by means of a generatorelectrode which produces iodine by electrochemical oxidation: 2I−⇒I₂+2e. Three replicates were obtained to ensure reproducibility.

5.2.6 Hotstage Microscopy

Hotstage microscopy was performed using a Linkam FTIR 600 hotstage witha TMS93 controller mounted on a Leica DM LP microscope equipped with aSpot Insight color camera for acquiring images. Images are acquiredusing Spot Advanced software version 4.5.9 build date Jun. 9, 2005,unless noted. The camera was white balanced prior to use. Samples wereobserved and acquired using a 20×0.40 N.A. long working distanceobjective with crossed polars and first order red compensator. Sampleswere placed on a coverslip. Another coverslip was then placed over thesample. Each sample was visually observed as the stage was heated. Thehotstage was calibrated using USP melting point standards.

5.2.7 Solid State Cross-Polarized Magic Angle Spinning ¹³C NuclearMagnetic Resonance Spectroscopy (¹³C CP/MAS ssNMR)

Samples were prepared for solid-state NMR spectroscopy by packing theminto 4 mm PENCIL type zirconia rotors. Scans were collected at ambienttemperature with a relaxation delay of 120.000 s, a pulse width of 2.2μs (90.0 deg), an acquisition time of 0.030 s, and a spectral width of44994.4 Hz (447.520 ppm). A total of 100 scans were collected. Crosspolarization was achieved with using ¹³C as the observed nucleus and ¹Has the decoupled nucleus with a contact time of 10.0 ms. A magic anglespinning rate of 12000 Hz was used. Spectra are externally referenced toglycine at 176.5 ppm.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims. All publications,patents and patent applications mentioned in this specification areherein incorporated by reference into the specification to the sameextent as if each individual publication, patent or patent applicationwas specifically and individually indicated to be incorporated herein byreference.

5.2.8 Single-Crystal X-ray Diffraction

Sample Preparation

The crystals utilized for Form A structure determination were preparedby sublimation of the Form A. The crystals were removed from the coldfinger after the sample was heated between 155-206° C. for approximately90 minutes. (Table 3 Experimental)

Data Collection

A colorless needle of C₁₅H₉FN₂O₃ having approximate dimensions of0.44×0.13×0.03 mm, was mounted on a glass fiber in random orientation.Preliminary examination and data collection were performed with Mo K_(α)radiation (λ=0.71073 Å) on a Nonius KappaCCD diffractometer. Refinementswere performed on an LINUX PC using SHELX97 (Sheldrick, G. M. SHELX97, AProgram for Crystal Structure Refinement, University of Gottingen,Germany, 1997).

Cell constants and an orientation matrix for data collection wereobtained from least-squares refinement using the setting angles of 13862reflections in the range 2°<θ<24°. The refined mosaicity fromDENZO/SCALEPACK (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276,307) was 0.33° indicating good crystal quality. The space group wasdetermined by the program XPREP (Bruker, XPREP in SHELXTL v. 6.12.,Bruker AXS Inc., Madison, Wis., USE, 2002). From the systematic presenceof the following conditions: h0l h+l=2n; 0k0 k=2n, and from subsequentleast-squares refinement, the space group was determined to be P2₁/n(no. 14).

The data were collected to a maximum 2 value of 2469°, at a temperatureof 150±1 K.

Data Reduction

Frames were integrated with DENZO-SMN (Otwinowski, Z.; Minor, W. MethodsEnzymol. 1997, 276, 307). A total of 13862 reflections were collected,of which 3201 were unique. Lorentz and polarization corrections wereapplied to the data. The linear absorption coefficient is 0.110 mm⁻¹ forMo K_(α) radiation. An empirical absorption correction using SCALEPACK(Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307) was applied.Transmission coefficients ranged from 0.951 to 0.997. A secondaryextinction correction was applied (Sheldrick, G. M. SHELX97, A Programfor Crystal Structure Refinement, University of Gottingen, Germany,1997). The final coefficient, refined in least-squares, was 0.0046 (inabsolute units). Intensities of equivalent reflections were averaged.The agreement factor for the averaging was 10.1% based on intensity.

Structure Solution and Refinement

The structure was solved by direct methods using SIR2004 (Burla, M. C.,et al., J. Appl. Cryst. 2005, 38, 381). The remaining atoms were locatedin succeeding difference Fourier syntheses. Hydrogen atoms were includedin the refinement but restrained to ride on the atom to which they arebonded. The structure was refined in full-matrix least-squares byminimizing the function:Σw(|F _(o)|² −|F _(c)|²)²

The weight w is defined as 1/[σ²(F_(o) ²)+(0.0975P)²+(0.0000P)], whereP=(F_(o) ²+2F_(c) ²)/3.

Scattering factors were taken from the “International Tables forCrystallography” (International Tables for Crystallography, Vol. C,Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables4.2.6.8 and 6.1.1.4). Of the 3201 reflections used in the refinements,only the reflections with F_(o) ²>2σ(F_(o) ²) were used in calculatingR. A total of 2010 reflections were used in the calculation. The finalcycle of refinement included 382 variable parameters and converged(largest parameter shift was <0.01 times its estimated standarddeviation) with unweighted and weighted agreement factors of:R=Σ|F _(o) −F _(c) |/ΣF _(o)=0.062R _(w)=√{square root over ((Σw(F _(o) ² −F _(c) ²)/Σw(F _(o)²)²))}=0.152

The standard deviation of an observation of unit weight was 1.01. Thehighest peak in the final difference Fourier had a height of 0.64 e/Å³.The minimum negative peak had a height of −0.33 e/Å³.

Calculated X-Ray Powder Diffraction (XRPD) Pattern

A calculated XRPD pattern was generated for Cu radiation usingPowderCell 2.3 (PowderCell for Windows Version 2.3 Kraus, W.; Nolze, G.Federal Institute for Materials Research and Testing, Berlin Germany, EU, 1999) and the atomic coordinates, space group, and unit cellparameters from the single crystal data.

ORTEP and Packing Diagrams

The ORTEP diagram was prepared using ORTEP III (Johnson, C. K. ORTEPIII,Report ORNL-6895, Oak Ridge National Laboratory, TN, U.S.A. 1996, andOPTEP-3 for Windows V1.05, Farrugia, L. J., J. Appl. Cryst. 1997, 30,565). Atoms are represented by 50% probability anisotropic thermalellipsoids. Packing diagrams were prepared using CAMERON (Watkin, D. J.et al., CAMERON, Chemical Crystallography Laboratory, University ofOxford, Oxford, 1996) modeling.

Results and Discussion

The monoclinic cell parameters and calculated volume of Form A are:a=24.2240(10) Å, b=3.74640(10) Å, c=27.4678(13) Å, α□=□90.00°,□β=92.9938(15)°, γ=90.00°, V=2489.38(17) Å³. The molecular weight is284.25 g/mol⁻¹ and Z=8 (where Z is the number of drug molecules perasymmetric unit) resulting in a calculated density (d_(calc), g cm⁻³) of1.517 g cm³ for this crystal structure. The space group was determinedto be P2₁/n (no. 14), which is an achiral space group. A summary of thecrystal data and crystallographic data collection parameters areprovided as follows:

formula C₁₅H₉FN₂O₃ formula weight 284.25 space group P 1 21/n 1 (No. 14)a, Å 24.2240(10) b, Å 3.74640(10) c, Å 27.4678(13) b, deg 92.9938(15) V,Å³ 2489.38(17) Z 8 d_(calc), g cm⁻³ 1.517 crystal dimensions, mm 0.44 ×0.13 × 0.03 temperature, K 150. radiation (wavelength, Å) Mo K_(a)(0.71073) monochromator graphite linear abs coef, mm⁻¹ 0.110 absorptioncorrection applied empirical transmission factors: min, max 0.951 to0.997 diffractometer Nonius KappaCCD h, k, l range 0 to 28 0 to 4 −32 to32 2q range, deg 4.45-49.38 mosaicity, deg 0.33 programs used SHELXTLF₀₀₀ 1168.0 weighting 1/[s²(F_(o) ²) + (0.0975P)² + 0.000P] where P =(F_(o) ² + 2F_(c) ²)/3 data collected 13862 unique data 3201 R_(int)0.101 data used in refinement 3201 cutoff used in R-factor calculationsF_(o) ² > 2.0s(F_(o) ²) data with I > 2.0s(I) 2010 refined extinctioncoef 0.0046 number of variables 382 largest shift/esd in final cycle0.00 R(F_(o)) 0.062 R_(w)(F_(o) ²) 0.152 goodness of fit 1.006

The quality of the structure obtained is high to moderate, as indicatedby the R-value of 0.062 (6.2%). Usually R-values in the range of 0.02 to0.06 are quoted for the most reliably determined structures. While thequality of the crystal structure is slightly outside the accepted rangefor most reliably determined structures, the data is of sufficientquality to ensure to location of the atomic positions in the molecularstructure is correct.

An ORTEP drawing of Form A is shown in FIG. 11. The asymmetric unitshown in contains a dimer of two molecules arranged to form a possiblehydrogen bond through the adjacent carboxylic acid groups. Since theacid protons were not located from the Fourier map it is assumed themolecules are neutral. A packing diagram of Form A, viewed down thecrystallographic b axis, is shown in FIG. 9.

The simulated XRPD pattern of Form A, shown in FIG. 10, was generatedfrom the single crystal data, and is in good agreement with theexperimental XRPD pattern of Form A (see, e.g., FIG. 1). Differences inintensities can arise from preferred orientation. Preferred orientationis the tendency for crystals, usually plates or needles, to alignthemselves with some degree of order. Preferred orientation can affectpeak intensities, but not peak positions, in XRPD patterns. Slightshifts in peak location can arise from the fact that the experimentalpowder pattern was collected at ambient temperature, and the singlecrystal data was collected at 150 K. Low temperatures are used in singlecrystal analysis to improve the quality of the structure.

Table 1 Shows the Fractional Atomic Coordinates for the Asymmetric Unitof Form A.

TABLE 1 Positional Parameters and Their Estimated Standard Deviationsfor Form A Atom x y z U(Å²) F(122) 0.43198(12) 0.7655(8) −0.17546(10)0.0487(10) F(222) −0.20343(15) 0.7129(10) 0.06378(14) 0.0781(14) O(13)0.42977(13) 0.4875(8) −0.08927(11) 0.0324(10) O(23) −0.12941(13)0.4507(9) 0.12653(12) 0.0402(10) O(151) 0.25519(13) 0.4795(9)0.10765(12) 0.0382(10) O(152) 0.29215(13) 0.2155(9) 0.17515(12)0.0403(10) O(251) 0.16226(13) 0.4813(9) 0.15012(12) 0.0385(10) O(252)0.19645(13) 0.1939(9) 0.21659(12) 0.0393(10) N(11) 0.35817(15) 0.5856(9)−0.04386(14) 0.0279(10) N(14) 0.44373(16) 0.3409(10) −0.04263(14)0.0327(12) N(21) −0.04134(16) 0.5165(9) 0.11065(14) 0.0305(12) N(24)−0.09772(17) 0.3201(11) 0.16787(15) 0.0388(14) C(12) 0.37827(18)0.6256(11) −0.08637(17) 0.0266(14) C(15) 0.40019(19) 0.4091(11)−0.01823(17) 0.0261(14) C(22) −0.0926(2) 0.5601(12) 0.09502(18)0.0319(15) C(25) −0.0471(2) 0.3690(11) 0.15580(17) 0.0302(15) C(121)0.35225(19) 0.7961(11) −0.12930(17) 0.0291(14) C(122) 0.3784(2)0.8567(12) −0.17244(18) 0.0345(15) C(123) 0.3519(2) 1.0117(12)−0.21257(19) 0.0407(17) C(124) 0.2973(2) 1.1101(13) −0.21014(19)0.0416(17) C(125) 0.2694(2) 1.0543(12) −0.1677(2) 0.0409(17) C(126)0.2966(2) 0.8996(12) −0.12784(18) 0.0349(15) C(151) 0.39702(19)0.3013(11) 0.03319(16) 0.0260(14) C(152) 0.34897(19) 0.3623(11)0.05704(16) 0.0261(15) C(153) 0.34631(18) 0.2594(11) 0.10554(16)0.0253(14) C(154) 0.39150(19) 0.0970(11) 0.13029(17) 0.0279(14) C(155)0.43977(19) 0.0412(11) 0.10614(17) 0.0291(15) C(156) 0.44250(19)0.1421(11) 0.05765(17) 0.0292(15) C(157) 0.2955(2) 0.3188(12)0.13209(18) 0.0312(15) C(221) −0.1109(2) 0.7083(12) 0.04727(19)0.0388(17) C(222) −0.1643(3) 0.7823(15) 0.0331(2) 0.053(2) C(223)−0.1825(3) 0.9272(15) −0.0122(3) 0.064(2) C(224) −0.1415(4) 0.9930(16)−0.0433(3) 0.068(3) C(225) −0.0870(3) 0.9202(15) −0.0316(2) 0.066(2)C(226) −0.0678(3) 0.7766(12) 0.01365(17) 0.0543(19) C(251) 0.00110(19)0.2695(11) 0.18877(17) 0.0300(15) C(252) 0.05426(19) 0.3352(11)0.17481(17) 0.0289(15) C(253) 0.09949(19) 0.2449(11) 0.20524(17)0.0277(15) C(254) 0.0919(2) 0.0940(11) 0.25087(17) 0.0296(15) C(255)0.0389(2) 0.0335(11) 0.26491(17) 0.0300(15) C(256) −0.0064(2) 0.1185(12)0.23430(17) 0.0322(15) C(257) 0.1559(2) 0.3165(12) 0.18902(17)0.0305(15) H(123) 0.371 1.050 −0.241 0.048 H(124) 0.278 1.217 −0.2380.050 H(125) 0.232 1.123 −0.166 0.049 H(126) 0.278 0.862 −0.099 0.042H(151) 0.227 0.491 0.125 0.057 H(152) 0.318 0.473 0.041 0.031 H(154)0.389 0.025 0.163 0.033 H(155) 0.471 −0.066 0.123 0.035 H(156) 0.4750.103 0.041 0.035 H(223) −0.220 0.975 −0.020 0.077 H(224) −0.151 1.094−0.074 0.082 H(225) −0.061 0.969 −0.055 0.080 H(226) −0.030 0.729 0.0210.065 H(252) 0.226 0.213 0.202 0.059 H(254) 0.123 0.034 0.272 0.035H(255) 0.033 −0.068 0.296 0.036 H(256) −0.043 0.074 0.244 0.039 H(25A)0.060 0.443 0.144 0.035 U_(eq) = (⅓)Σ_(ι)Σ_(j)U_(ij)a*_(i)a*_(j)a_(i).a_(j)

Hydrogen Atoms are Included in Calculation of Structure Factors but notRefined

TABLE 2 Peak Positions of Form A from Calculated XRPD Pattern Generatedfrom Single Crystal Data Position (°2θ)^(a) d-spacing I/Io^(c) 4.7418.63 3.24 4.99 17.69 20.99 6.44 13.72 4.46 7.30 12.10 6.46 10.15 8.7032.47 10.51 8.41 1.90 11.27 7.85 6.14 11.59 7.63 13.97 12.90 6.86 15.0514.25 6.21 100.00 14.50 6.10 8.25 14.64 6.05 75.70 15.17 5.84 65.1215.69 5.64 47.56 16.31 5.43 8.61 16.37 5.41 8.11 16.74 5.29 14.82 18.444.81 2.04 18.78 4.72 3.13 19.04 4.66 4.05 19.07 4.65 3.81 19.40 4.572.85 20.03 4.43 11.28 20.06 4.42 5.41 20.30 4.37 1.92 20.39 4.35 10.8721.11 4.20 21.30 21.20 4.19 7.07 22.03 4.03 4.07 22.64 3.92 4.72 23.163.84 4.71 23.86 3.73 2.64 23.95 3.71 9.76 24.21 3.67 12.14 24.27 3.6732.98 24.61 3.61 61.89 24.84 3.58 3.05 24.86 3.58 8.00 24.94 3.57 7.1525.00 3.56 2.17 25.02 3.56 2.09 25.13 3.54 10.36 25.61 3.48 1.67 25.793.45 3.04 25.87 3.44 25.14 26.02 3.42 15.19 26.20 3.40 3.41 26.48 3.3610.64 26.87 3.31 3.11 26.87 3.32 5.65 27.08 3.29 5.60 27.10 3.29 33.7127.16 3.28 93.68 27.26 3.27 82.52 27.45 3.25 4.42 27.92 3.19 5.61 28.053.18 3.96 28.20 3.16 59.41 28.28 3.15 3.04 28.53 3.13 6.29 28.83 3.0913.36 28.93 3.08 15.74 28.96 3.08 6.42 29.05 3.07 3.93 29.18 3.06 2.4229.24 3.05 2.10 29.42 3.03 2.64 29.52 3.02 2.19 29.57 3.02 15.65 29.942.98 2.66 30.00 2.98 4.98 30.43 2.94 1.68 30.58 2.92 1.21 30.79 2.901.79 30.93 2.89 1.07 31.07 2.88 3.23 31.18 2.87 7.65 31.42 2.84 2.6831.97 2.80 2.16 32.46 2.76 1.99 32.65 2.74 1.23 32.88 2.72 1.02 33.132.70 2.89 33.17 2.70 4.30 33.40 2.68 2.97 33.64 2.66 2.39 33.90 2.641.46 34.25 2.62 2.54 34.74 2.58 1.40 35.18 2.55 1.60 35.59 2.52 1.2135.96 2.50 1.50 36.64 2.45 7.44 ^(a)I/I_(o) = relative intensity b.Peaks having I/I_(o) = relative intensity less than 1 and peak positionsgreater than 36.6 °2θ are not displayed

TABLE 3 Peak Positions of Form A Experimental XRPD Pattern Position(°2θ)^(a) d-spacing I I/Io^(c) 4.96 17.79 59 4 6.39 13.83 52 4 10.108.75 417 31 11.54 7.66 144 11 12.62 7.01 101 7 12.81 6.91 341 25 13.926.36 197 14 14.16 6.25 737 54 14.55 6.08 621 46 14.88 5.95 379 28 15.075.87 1364 100 15.58 5.68 223 16 16.27 5.44 288 21 16.61 5.33 405 3018.74 4.73 52 4 18.94 4.68 84 6 19.28 4.60 115 8 19.94 4.45 248 18 20.274.38 240 18 20.74 4.28 131 10 20.97 4.23 602 44 21.22 4.18 126 9 21.934.05 44 3 22.58 3.93 60 4 22.80 3.90 88 6 23.00 3.86 146 11 23.79 3.74173 13 24.14 3.68 161 12 24.46 3.64 61 4 25.44 3.50 104 8 25.64 3.47 876 26.07 3.42 111 8 26.34 3.38 100 7 26.74 3.33 559 41 27.06 3.29 55 427.79 3.21 173 13 28.42 3.14 154 11 29.09 3.07 63 5 30.48 2.93 55 4^(a)I/I_(o) = relative intensity b. Bold denotes characteristic peak set(no peaks within 0.2 °2θ relative to PTC124 Form B files 169490, 172972,172173, 170901, 169284, and 168717.

TABLE 4 Peak Positions of Form B XRPD Pattern (file 169490) Position(°2θ)^(a) d-spacing I I/Io^(c) 6.14 14.38 73 7 6.39 13.82 386 35 6.9612.70 57 5 7.92 11.16 171 15 10.78 8.20 163 15 12.44 7.11 66 6 12.617.01 163 15 12.88 6.87 41 4 13.52 6.54 261 23 13.78 6.42 351 31 13.976.33 1115 100 14.30 6.19 35 3 15.46 5.73 46 4 15.68 5.65 227 20 15.895.57 754 68 16.33 5.42 204 18 16.76 5.29 105 9 17.03 5.20 485 43 20.104.41 603 54 21.03 4.22 110 10 23.34 3.81 42 4 23.86 3.73 199 18 24.183.68 294 26 24.42 3.64 120 11 24.64 3.61 49 4 26.62 3.35 121 11 26.963.30 134 12 27.29 3.27 949 85 27.64 3.22 155 14 27.96 3.19 93 8 28.813.10 101 9 31.05 2.88 55 5 32.38 2.76 43 4 32.58 2.75 39 3 36.23 2.48 898 37.81 2.38 38 3 38.28 2.35 53 5 38.44 2.34 83 7 39.16 2.30 45 4^(a)I/I_(o) = relative intensity. b. Bold denotes characteristic peakset compared to Form A.

TABLE 5 Peak Positions of Form B (shifted 1) XRPD Pattern (file 168717)Position (°2θ)^(a) d-spacing I I/Io^(c) 6.42 13.75 214 34 7.00 12.63 234 7.89 11.20 98 15 10.85 8.15 97 15 12.61 7.01 117 18 12.92 6.85 29 513.47 6.57 208 33 13.97 6.33 558 88 15.81 5.60 635 100 16.45 5.38 143 2317.12 5.18 320 50 20.05 4.42 544 86 21.05 4.22 66 10 23.92 3.72 110 1724.28 3.66 21 3 27.00 3.30 48 8 27.39 3.25 126 20 27.84 3.20 32 5 28.043.18 68 11 28.94 3.08 90 14 31.10 2.87 35 6 32.58 2.75 42 7 36.11 2.4989 14 37.71 2.38 19 3 38.15 2.36 20 3 38.61 2.33 52 8 ^(a)I/I_(o) =relative intensity b. Bold denotes characteristic peak set compared toForm A.

TABLE 6 Peak Positions of Form B (shifted 2) XRPD Pattern (file 172972)Position (°2θ)^(a) d-spacing I I/Io^(c) 6.10 14.48 155 3 6.38 13.84 106823 6.54 13.50 1371 29 7.10 12.44 270 6 8.02 11.02 653 14 10.91 8.11 3768 12.71 6.96 195 4 13.50 6.55 601 13 13.62 6.50 404 9 13.86 6.38 702 1514.10 6.27 4633 99 15.56 5.69 158 3 15.70 5.64 402 9 15.91 5.57 3422 7316.55 5.35 673 14 16.96 5.22 283 6 17.22 5.15 1639 35 17.50 5.06 150 319.82 4.48 242 5 20.08 4.42 1950 42 20.34 4.36 209 4 21.15 4.20 718 1523.78 3.74 208 4 23.93 3.72 508 11 24.38 3.65 412 9 24.56 3.62 184 426.88 3.31 198 4 27.16 3.28 219 5 27.48 3.24 4657 100 27.88 3.20 231 528.04 3.18 183 4 28.78 3.10 353 8 29.02 3.07 948 20 32.71 2.74 233 536.01 2.49 639 14 38.10 2.36 253 5 38.56 2.33 216 5 39.38 2.29 179 4^(a)I/I_(o) = relative intensity b. Bold denotes characteristic peak setcompared to Form A.

TABLE 7 Peak Positions of Form B (shifted 3) XRPD Pattern (file 172173)Position (°2θ)^(a) d-spacing I I/Io^(c) 1.79 49.38 398 3 2.30 38.42 10029 2.57 34.38 1008 9 2.78 31.78 974 8 3.29 26.85 786 7 3.59 24.61 739 63.89 22.71 634 5 4.07 21.71 617 5 4.34 20.35 553 5 4.49 19.67 476 4 4.7618.56 415 4 5.06 17.46 347 3 6.47 13.66 9496 82 6.91 12.79 1606 14 7.9611.09 2771 24 10.89 8.12 3389 29 12.87 6.87 2022 18 13.58 6.52 381 313.99 6.32 4752 41 15.97 5.55 1724 15 16.48 5.38 752 7 17.10 5.18 179016 20.00 4.44 505 4 20.36 4.36 1069 9 21.04 4.22 501 4 23.40 3.80 906 824.29 3.66 6591 57 24.89 3.57 522 5 26.87 3.32 1823 16 27.49 3.24 11543100 27.80 3.21 1924 17 28.07 3.18 353 3 29.08 3.07 434 4 38.61 2.33 3763 ^(a)I/I_(o) = relative intensity. b. Bold denotes characteristic peakset compared to Form A.

TABLE 8 Peak Positions of Form B (PO) XRPD Pattern (file 170901)Position (°2θ)^(a) d-spacing I I/Io^(c) 6.22 14.20 356 8 6.51 13.57 133230 7.13 12.39 171 4 8.17 10.81 727 17 10.91 8.11 484 11 12.87 6.87 355 813.80 6.41 930 21 14.12 6.27 4251 97 14.28 6.20 2569 59 15.78 5.61 172 416.23 5.46 4368 100 16.54 5.36 684 16 17.15 5.17 1377 32 20.33 4.36 105724 21.22 4.18 475 11 21.36 4.16 290 7 23.94 3.71 578 13 24.30 3.66 201 527.30 3.26 217 5 27.58 3.23 303 7 28.00 3.18 262 6 28.74 3.10 239 528.96 3.08 327 7 32.70 2.74 224 5 36.74 2.44 265 6 38.18 2.36 175 438.38 2.34 227 5 38.52 2.34 160 4 39.31 2.29 142 3 ^(a)I/I_(o) =relative intensity. b. Bold denotes characteristic peak set compared toForm A.

TABLE 9 Peak Positions of Form B shifted XRPD Pattern (file 169284)Position (°2θ)^(a) d-spacing I I/Io^(c) 6.04 14.62 102 5 6.49 13.61 2151100 7.91 11.17 240 11 10.92 8.10 252 12 12.61 7.01 304 14 12.92 6.85 26312 13.10 6.75 71 3 13.42 6.59 103 5 13.82 6.40 177 8 13.99 6.32 565 2615.40 5.75 99 5 15.76 5.62 1580 73 16.51 5.37 516 24 17.15 5.17 334 1619.92 4.45 606 28 20.04 4.43 624 29 21.01 4.23 101 5 23.92 3.72 80 424.28 3.66 285 13 24.48 3.63 81 4 26.77 3.33 161 7 27.14 3.28 259 1227.40 3.25 1413 66 27.74 3.21 175 8 28.09 3.17 122 6 28.82 3.10 165 828.99 3.08 488 23 31.03 2.88 118 5 32.58 2.75 271 13 35.64 2.52 155 735.85 2.50 329 15 37.48 2.40 72 3 37.66 2.39 89 4 38.62 2.33 84 4^(a)I/I_(o) = relative intensity. b. Bold denotes characteristic peakset compared to Form A.

What is claimed is:
 1. A method for treating retinitis pigmentosa comprising administering to a patient having retinitis pigmentosa a crystal form of the compound of formula (I):

which has an X-ray powder diffraction pattern comprising at least three peak positions (°2θ±0.2) when measured using Cu Kα radiation, selected from the group consisting of 4.96, 6.39, 10.10, 11.54, 12.62, 12.81, 13.92, 14.16, 14.55, 14.88, 15.07, 15.58, 16.27, 16.61, 18.74, 18.94, 19.28, 19.94, 20.27, 20.74, 20.97, 21.22, 21.93, 22.58, 22.80, 23.00, 23.79, 24.14, 24.46, 25.44, 25.64, 26.07, 26.34, 26.74, 27.06, 27.79, 28.42, 29.09 and 30.48, comprising obtaining said crystal form of the compound of formula (I) and subsequently administering said crystal form of the compound of formula (I) to said patient.
 2. The method of claim 1, wherein the crystal form has the following unit cell parameters when measured at 150 K: a=24.2240 Å; b=3.74640 Å; c=27.4678 Å; α=90°; β=92.9938°; γ=90°; V=2489.38(17) Å³; Z=8; calculated density (d_(calc), g cm⁻³) is 1.517 g cm³; and the space group is P2₁/n (no. 14).
 3. The method of claim 1, wherein the crystal form has an X-ray powder diffraction pattern comprising at least one peak position (°2θ±0.2) when measured using Cu Kα radiation, selected from the group consisting of 10.10, 11.54, 14.55, 14.88 and 15.07.
 4. The method of claim 3, wherein the crystal form has a differential scanning calorimetry thermogram which has an endothermic event with a peak temperature at 244° C.
 5. The method of claim 3, wherein the crystal form has a thermogravimetric analysis thermogram which has a mass loss of less than 1% of the total mass of the sample upon heating from 33° C. to 205° C.
 6. The method of claim 2, wherein the crystal form is non-hygroscopic.
 7. The method of claim 1, wherein the crystal form is characterized by ¹³C CP/MAS solid-state NMR signals at the following positions: 172.6, 167.0, 131.3, 128.4 and 117.1 ppm, when externally referenced to glycine at 176.5 ppm.
 8. The method of claim 1, wherein the crystal form has an X-ray powder diffraction pattern comprising peak positions (°2θ+0.2) when measured using Cu Kα radiation, of 10.10, 11.54, 14.55, 14.88 and 15.07.
 9. The method of claim 1, wherein the crystal form has a purity of greater than 90%. 